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The roles of mDia2 in hematopoietic stem and progenitor cell engraftment and migration

mDia2 在造血干细胞和祖细胞植入和迁移中的作用

基本信息

批准号：
10377496
负责人：
Peng Ji
金额：
$ 50.69万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377496
关键词：
Acetylation Actins Adhesions Affect Agonist Benign Biochemical Biological Assay Blood Cells Bone Marrow Bone Marrow Cell Transplantation Bone Marrow Stem Cell Bone Marrow Transplantation CD18 Antigens CD34 gene CSF3 gene Cell Adhesion Cell Lineage Cell Transplantation Cells Clinical Collaborations Colony-Stimulating Factors Complex Cytoskeleton Data Deacetylase Defect Disease Engraftment F-Actin Failure Family Genes Genetic Goals Graft Rejection HDAC6 gene Hematological Disease Hematopoietic Hematopoietic Stem Cell Mobilization Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human ITGAM gene ITGB2 gene Immune In Vitro Integrins Investigation Knock-out Knockout Mice Lead Lysine Malignant - descriptor Mammals Mediating Microfilaments Mus Pathway interactions Pattern Phosphorylation Play Post-Translational Protein Processing Pre-Clinical Model Process Progenitor Cell Engraftment Protein Family Proteins Publishing Regulation Reporting Research Personnel Rho-associated kinase Role Serum Response Factor Signal Pathway Signal Transduction Pathway Stem cell transplant Testing Transcriptional Regulation Transplantation Wasps base cell motility differential expression experimental study gang hematopoietic engraftment improved in vivo migration mouse model mutant new therapeutic target non-histone protein novel overexpression polymerization response stem cell engraftment stem cell function stem cell migration stem cell population targeted treatment translational potential

项目摘要

PROJECT SUMMARY Failure in engraftment is one of the major limitations of hematopoietic stem cell transplantation, which is critical for the treatment of many benign and malignant hematologic disorders. Besides immune-mediated rejection of the transplanted cells, ineffective migration, adhesion, and engraftment of the hematopoietic stem and progenitor cells (HSPCs) to the bone marrow niche are important causes of engraftment failure. The intracellular signaling pathways regulating HSPC engraftment and migration to the bone marrow often directly or indirectly target the actin cytoskeleton network through proteins that regulate actin polymerization. The mDia formins are a major actin-nucleating family, but their functions in HSPCs are unknown. Our preliminary studies using our recently generated mDia2 hematopoietic-specific knockout mice showed that loss of mDia2 resulted in significant defects in HSPC adhesion and bone marrow engraftment in competitive transplantation assays. Loss of mDia2 also markedly reduced G-CSF-induced HSPC mobilization out of the bone marrow. We also found that beta2 integrins including CD11a/CD18 (LFA1) and CD11b/CD18 (Mac1) were significantly downregulated with the loss of mDia2. These results led us to hypothesize that mDia2 is critical for the engraftment, adhesion, and migration of the hematopoietic stem and progenitor cells. We proposed three specific aims to test this hypothesis. First, we will determine the functional roles of mDia2 in HSPC engraftment, adhesion, and migration to the bone marrow. Specifically, we will investigate the role of mDia2 in the in vitro and in vivo migration and adhesion of HSPCs and their relationship with the bone marrow niche. We will also use an mDia activator in vivo to explore a pre-clinical model of mDia activation for enhancing stem cell mobilization and engraftment. In these experiments, relatively pure SLAM+ hematopoietic stem cell population will also be tested. Second, we will determine the mechanisms of mDia2 in regulating HSPC engraftment, adhesion, and migration through a novel mDia2-MAL-SRF-LFA1/Mac1 pathway. Third, based on our preliminary studies that acetylation of mDia2 affects its activity in actin polymerization, we will determine whether and how acetylation or other post-translational modifications of mDia2 influence its functions in HSPC engraftment and migration. The overall goal of this proposed study is to understand the roles of mDia2 in HSPC engraftment, adhesion, and migration and elucidate its mechanisms using in vivo mouse models and transplantation assays. A better understanding of these processes may lead to the identification of novel targets for therapeutic strategies in hematopoietic stem cell transplantation.

项目总结